HA-1 T TCR T Cell Immunotherapy for the Treatment of Patients With Relapsed or Refractory Acute Leukemia After Donor Stem Cell Transplant

Official title

Phase I Study of Adoptive Immunotherapy With CD8+ and CD4+ Memory T Cells Transduced to Express an HA-1-Specific T Cell Receptor (TCR) for Children and Adults With Recurrent Acute Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (HCT)

Overview

This phase I trial studies the side effects and best dose of CD4+ and CD8+ HA-1 T cell receptor (TCR) (HA-1 T TCR) T cells in treating patients with acute leukemia that persists, has come back (recurrent) or does not respond to treatment (refractory) following donor stem cell transplant. T cell receptor is a special protein on T cells that helps them recognize proteins on other cells including leukemia. HA-1 is a protein that is present on the surface of some peoples' blood cells, including leukemia. HA-1 T cell immunotherapy enables genes to be added to the donor cells to make them recognize HA-1 markers on leukemia cells.

Detailed description

OUTLINE:

This is a dose-escalation study of CD4+ and CD8+ HA-1 TCR T cells.

Patients receive lymphodepleting chemotherapy (e.g., fludarabine and cyclophosphamide or debulking regimens as specified in the protocol) ending 2-14 days prior to HA-1 TCR T cell administration. Patients then receive CD4+ and CD8+ HA-1 TCR T cells intravenously (IV).

After completion of study treatment, patients are followed up closely for 12 weeks and then every 6 months for years 1-5, and every year for years 6-15.

Initial study activity was funded in part by HighPass Bio, Inc. Current study activity is funded in part by PromiCell Therapeutics, Inc.

Interventions

• Biological CD8+ and CD4+ Donor Memory T-cells-expressing HA1-Specific TCR
  Given IV
• Procedure Bone Marrow Aspiration
  Undergo bone marrow aspiration
• Procedure Biospecimen Collection
  Undergo blood sample collection

Primary outcome measures

• Feasibility of manufacturing minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells [Time frame: At time of T cell infusion (at day 0)]
• Feasibility of administering minor H antigen (HA-1) T cell receptor (TCR) CD8+ and CD4+ T cells [Time frame: At time of T cell infusion (at day 0)]
• Incidence of dose-limiting toxicities of HA-1 T cell receptor (TCR) T cells [Time frame: Up to 12 weeks after T-cell infusion]

Secondary outcome measures (9)

• Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD4+ T cells in peripheral blood [Time frame: Up to 1 year]
• Duration of in vivo persistence of transferred HA-1 T cell receptor (TCR) CD8+ T cells in peripheral blood [Time frame: Up to 1 year]
• Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD4+ T cells in the bone marrow [Time frame: Up to 1 year]
• Presence, proportion and persistence of HA-1 T cell receptor (TCR) CD8+ T cells in the bone marrow [Time frame: Up to 1 year]
• Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells before adoptive T cell transfer [Time frame: At the time of T cell infusion (at day 0)]
• Specific cytolytic activity of HA-1 T cell receptor (TCR) CD8+ and CD4+ T cells against HLA-A*0201+ HA-1+ target cells after adoptive T cell transfer [Time frame: Up to 1 year]
• Reduction of leukemia in the bone marrow in subjects who have measurable leukemia in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion [Time frame: Up to 1 year]
• Reduction of recipient normal hematopoietic cells in the bone marrow in subjects who have measurable recipient normal hematopoietic cells in the marrow prior to HA-1 T cell receptor (TCR) T cell infusion [Time frame: Up to 1 year]
• Proportion of subjects who develop new or recurrent symptoms or signs of graft-versus-host disease [Time frame: Up to 1 year]

Eligibility criteria

Inclusion criteria

• Subject age 0-80 years at the time of enrollment.
• Subject must express HLA-A\*0201
• Subject must have the HA-1(H) genotype (RS\_1801284: A/G, A/A)
• Subject must have an adult donor for HCT who is adequately HLA matched by institutional standards (includes HLA-matched related or unrelated donors, and HLA-mismatched family donors, including haploidentical donors) and is either:

• HLA-A\*0201 positive and HA-1(H) negative (RS\_1801284: G/G) or
• HLA-A\*0201 negative
• Subjects who are currently undergoing or who previously underwent allogeneic HCT for

• Acute myeloid leukemia (AML) of any subtype
• Acute lymphoid leukemia (ALL) of any subtype
• Mixed phenotype/undifferentiated/any other type of acute leukemia, including blastic plasmacytoid dendritic cell neoplasm
• Chronic myeloid leukemia with a history of blast crisis and:

• With relapse or refractory disease (>= 5% marrow blasts, or circulating blasts) at any time after HCT
• With persistent rising minimal residual disease (defined as detectable disease by morphology, flow cytometry, molecular or cytogenetic testing but < 5% marrow blasts by morphology, no circulating blasts on >= 2 of two consecutive tests), refractory or ineligible for treatment with tyrosine kinase inhibitors at any time after HCT
• Myelodysplastic syndrome (MDS) of any subtype
• Chronic myelomonocytic leukemia (CMML)
• Juvenile myelomonocytic leukemia (JMML)
• Subjects must be able to understand and be willing to give informed consent; decision-impaired adults may consent with their legally authorized representative; parent or legal representative will be asked to consent for subjects younger than 18 years old
• Subjects must agree to participate in long-term follow-up for up to 15 years if they are enrolled in the study and receive T cell infusion
• Subjects who have relapsed or have MRD after HCT may receive other agents for treatment of disease and remain eligible for the protocol
• A specific performance status score is not required for enrolling on the protocol; a delay in infusion of the HA-1 TCR T cells may be required for subjects with low performance status

DONOR SELECTION INCLUSION

• Donor age >= 18 years
• Donors must be able to give informed consent

Exclusion criteria

• Medical or psychological conditions that would make the subject unsuitable candidate for cell therapy at the discretion of the principal investigator (PI)
• Fertile subjects unwilling to use contraception during and for 12 months after treatment
• Subjects with a life expectancy of < 3 months of enrollment from coexisting disease other than leukemia
• Subjects who have ongoing grade IV acute GVHD or severe chronic GVHD following most recent transplant. Exception: the principal investigator (PI) may make an exception on a case-by-case basis to include such a subject if there is doubt surrounding the GVHD diagnosis and/or sustained significant improvement in GVHD severity
• The presence of organ toxicities will not necessarily exclude subjects from enrolling on the protocol at the discretion of the PI; however, a delay in the infusion of HA-1 TCR T cells may be required

DONOR SELECTION EXCLUSION

• Donors who are human immunodeficiency virus (HIV)-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
• Unrelated donor residing outside of the United States of America (USA) unless the donor screening, testing and leukapheresis occur at an National Marrow Donor Program (NMDP)-affiliated and qualified donor center and are facilitated by the NMDP

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Fred Hutch/University of Washington Cancer Consortium — Seattle

Publications

• Krakow EF, Brault M, Summers C, Cunningham TM, Biernacki MA, Black RG, Woodward KB, Vartanian N, Kanaan SB, Yeh AC, Dossa RG, Bar M, Cassaday RD, Dahlberg A, Till BG, Denker AE, Yeung CCS, Gooley TA, Maloney DG, Riddell SR, Greenberg PD, Chapuis AG, Newell EW, Furlan SN, Bleakley M. HA-1-targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation. B PMID 38683966

Identifiers

NCT: NCT03326921 · 9716 · NCI-2017-01054 · 9716 · RG9217022

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗